Quantitative method and apparatus for measuring QT intervals from ambulatory electrocardiographic recordings

ABSTRACT

A quantitative method and apparatus for measuring a cardiac function interval. Beat-to-beat data representative of a cardiac interval is collected over an extended period of time. A series of bins, each of which has a defined value range, is defined. The collected data is organized into the bins in accordance with the value of the data and the value range of the bin. The percentage of data in each bin may be calculated based upon the quantity of data in each bin.

FIELD OF THE INVENTION

[0001] The present invention relates to measuring a cardiac functioninterval.

BACKGROUND OF THE INVENTION

[0002] It is known that prolongation of the QT interval may be a markerfor sudden death. Measurements of the QT interval are generally takenfrom a 12-lead electrocardiogram. The 12-lead electrocardiogram providesonly point-in-time data, thus missing the beat-to-beat dynamicity dataavailable from a Holter recording. Heretofore, beat-to-beat data hasbeen averaged due primarily to constraints in computing power.Unfortunately, averaging minimizes the understanding of the beat-to-beatvariability inherent in QT interval data.

[0003] Increases in the QT and QTc intervals of a 12-leadElectrocardiogram (ECG) are associated with an increased risk of cardiacdysrhythmias and sudden cardiac death. See, for example, Algra A,Tijssen J G P, Roelandt R T C, Pool J, Lubsen J: QTc Prolongationmeasured by standard 12-lead electrocardiography is an independent riskfactor for sudden death due to cardiac arrest. Circulation 83:1888,1991; Schwartz P J, Wolf S: Q T interval prolongation as predictor ofsudden death in patients with myocardial infarction. Circulation57:1074, 1978; Sawicki P T, Dahne R, Bender R, Berger M: Prolonged QTinterval as a predictor of mortality in diabetic neuropathy.Diabetologia 39:77, 1996.

[0004] While the resting 12-lead electrocardiogram may provide importantspatial information regarding the status of ventricular repolarization,the use of a single 12-lead ECG measured randomly in time may disregardpotentially important prognostic data regarding the dynamicity, temporalrelationships, and circadian rhythms of the QT interval.

[0005] It is known that the QT and QTc intervals may undergo significantchanges over both the shorter and longer term due to circadian rhythms.See, for example, Yi G, Guo X, Reardon M, Gallagher M M, Hnatkova K,Camm A J, Malik M: Circadian variation of the QT interval in patientswith sudden cardiac death after myocardial infarction. Am J Cardiol81:950, 1998.

[0006] It is known that the QT and QTc intervals may undergo significantchanges over both the shorter and longer term due to autonomic control.See, for example, Cappatto R, Alboni P, Pedroni P, Gilli G, AntoniolliG: Sympathetic and vagal influences on rate-dependent changes of QTinterval in healthy subjects. Am J Cardiol 68:1188, 1991; Browne K F,Zipes D I P, Heger J J, Prystowsky E N: Influence of the autonomicnervous system on the Q-T interval in man. Am J Cardiol 50:1099, 1982;Kautzner J, Hartikainen J E K, Heald S, Camm A J, Malik M: The effectsof reflex parasympathetic stimulation on the QT interval and QTdispersion. Am J Cardiol 80:1229, 1997.

[0007] A single 12-lead ECG taken at a given point in time may providemisleading and inaccurate cardiac risk data. Therefore, analysis of theQT interval for an entire 24-hour period may provide additionalinformation regarding the risk of sudden death not available on thesingle, random 12-lead ECG.

[0008] Recently, it has become possible to measure the QT interval on24-hour Holter (AECG) recordings. These measurements have generally beenreported as averages over short time periods, typically between about 15seconds and about five minutes. See, for example; Molnar J, Zhang F,Weiss J, Ehlert F A, Rosenthal J E: Diurnal Pattern of QTc Interval: Howlong is prolonged? Possible relation to circadian triggers ofcardiovascular events. J Am Coll Card 27:76, 1996; Yanaga T, Maruyama T,Kumanomido A, Adachi M, Noguchi S, Taguchi J: Usefulness of automaticmeasurement of QT interval using Holter tape in patients withhyperthyroidism. J Am Monit 6:27, 1993.

[0009] More recently beat-to-beat QT interval measurements have beenused. The use of averaged QT measurements may obscure significantshort-term variations in the TO intervals. Conversely, beat-to-beatmeasurements retain the natural variability data that may be importantfor calculating a patient's risk of dysrhythmia and sudden death.

[0010] Although beat-to-beat variability of the QT interval has beendescribed by Berger and others (see Berger R D, Kasper E K, Baughman KL, Marban E, Calkins H, Tomaselli G F: Beat-to-beat QT intervalvariability: Novel evidence for repolarization lability in ischemic andnonischemic dilated cardiomyopathy. Circulation 96:1557, 1997), littleis known regarding normal ranges in variability and measures of the QTinterval over a 24-hour period using beat-to-beat measurements.

[0011] Molnar and colleagues published a study that gives someindication of the dynamic range of the QT intervals. They reported amean maximum QTc interval of 495 ms for normal subjects using 24-hourambulatory monitoring. They also showed a mean intra-subject change of95 ms. Molnar further reported six normal female subjects as having amaximum mean QTc interval measurement of more than 500 ms. These meanmaximum measures were taken over a five minute period. They did notreport on the number of beats with a QTc that exceeded 0.45 seconds.

[0012] Morganroth and colleagues, using a manual analysis of Holter ECGrecordings, found that most normal subjects had QTc intervals of greaterthen 0.45 seconds at some period during the 24-hour recording. SeeMorganroth J, Brozovich F V, McDonald J T, Jacobs R A: Variability ofthe QT measurement in healthy men, with implications for selection of anabnormal QT value to predict drug toxicity and proarrhythmia. Am JCardiol 67:774, 1991.

[0013] The use of mean QTc measurements tends to obscure the individualbeats that may exceed traditional normal values for QT and QTc. Whiletraditional measurements, such as measures of central tendency, havebeen used extensively to describe the relationship of QT and QTcmeasurements to a so-called normal value, these measurements tend toignore temporal dynamicity inherent in cardiac function. Thesemeasurements may be important to give an overall picture of the statusof the subject, however.

[0014] It has long been recognized that prolongation of the QT intervalmay be related to sudden death in a variety of clinical syndromes. Theexact relationship, however, has been difficult to define, partlybecause the QT interval is a dynamic measurement and changes have beenobserved in both the shorter term (beat-to-beat) and in the longer term(circadian rhythm).

[0015] A consistent manual measurement of the QT interval on the resting12-lead ECG can be imprecise and non-reproducible. Savelieva et al.showed that there was a high degree of variability when usinghand-measurements of the QT interval on the 12-lead ECG. See Savelieva1, Yi G, Guo X, Hnatkova K, Malik M: Agreement and reproducibility ofautomatic versus manual measurement of QT interval and QT dispersion. AmJ Cardiol 81:471, 1998. Applicants agree with the conclusions ofSavelieva and colleagues that automated measurements offer a higherdegree of consistency and reliability than manual measurements.

[0016] Traditionally, the QT interval has been measured on a resting12-lead ECG. In general, this method involves a manual estimation of theonset of the Q-wave and determination of the end of the T-wave. Severalbeats are used to determine the QT interval. One advantage of measuringthe QT interval on a resting 12-lead ECG is that lead placement isgenerally consistent and a full range of electrocardiographicfrequencies may be available for measurement. One disadvantage ofmeasuring the OT interval on a resting 12-lead ECG is related to theshort observation period. The QT interval may be subject to dynamicchange on both a beat-to-beat basis and over time, particularlydisplaying changes in circadian rhythm and in response to alteration ofautonomic function. Accordingly, a 12-lead ECG may not reflect the truestate of the QT interval, but only a representation at a single point intime.

[0017] Up to now, a method to measure the beat-to-beat variation of theQT interval on 24-hourAECG tapes has been unavailable. Most previousstudies have focused on average QT interval measurements over severalseconds or minutes, rather than individual beat-to-beat measurements.

[0018] There have been several attempts to measure the QT interval on24-hour AECG recordings using a variety of Holter analysis systems. Thesampling rate of these Holter analyzers has varied from about 125 Hz toabout 200 Hz, at both 8 bit and 12-bit resolution. In addition, thesesystems have used averages of both RR and QT intervals to overcomedata-processing problems. These averages have ranged from about 6seconds to about 5 minutes. The use of averages tends to obscurebeat-to-beat dynamic changes in QT and QTc intervals. For example,normal subjects have some beats with increased QT and QTc measurements,and subjects with known ILQT may have many normal QT and QTcmeasurements.

[0019] It is an objective of the present invention, in a preferredembodiment, to enable the assessment of the QT and QTc intervals andother cardiac function intervals on a beat-to-beat basis, providing aquantitative index of the percentage of individual beats with QT and QTcintervals.

[0020] It is another objective of the present invention, in a preferredembodiment, to enable the measurement and assessment of the QT and QTcintervals and other cardiac function intervals over an extended periodof time, including not only periods of time greater than about oneminute but also periods of time lasting at least 24 hours and evenlonger, in some cases.

SUMMARY OF THE INVENTION

[0021] In accordance with the present invention, in a preferredembodiment, this and other objectives are achieved by providing a methodand apparatus for analyzing beat-to-beat QT intervals fromhigh-resolution Ambulatory Electrocardiographic monitoring (AECG) todetect the percentage of beats in a prolonged AECG recording that exceeda discrete time-based threshold. Beat-to-beat QT and RR intervals may bemeasured to calculate beat-to-beat QTc. In a preferred embodiment, thepercentage of beats in which the QT and QTc intervals exceed 0.45seconds (% QT and % QTc) may be examined.

[0022] The present invention, in a preferred embodiment, provides amethod and apparatus to analyze beat-to-beat QT data, stratify the dataaccording to a time-series bin-array, and calculate the percentage ofbeats that fall outside a predetermined, user-defined threshold. Thismethod and apparatus may be applicable to a wide variety of differentsubjects including, for example, normal subjects, subjects with long QTsyndrome (ILQTS), and drug titration studies.

[0023] Further objects, advantages and other features of the presentinvention will be apparent to those skilled in the art upon reading thedisclosure set forth herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0024] A detailed description of a preferred embodiment of the presentinvention will be made with reference to the accompanying drawings.

[0025]FIG. 1 illustrates an example of a mathematical formula forconstructing a bin for calculating a QT index in accordance with oneembodiment of the present invention.

[0026]FIG. 2 illustrates an example of a mathematical formula forconstructing a bin for calculating a QTc index in accordance with oneembodiment of the present invention.

[0027]FIG. 3 illustrates an example of ECG fiducial points and acomputer generated QT interval with a cursor in place.

[0028]FIG. 4 illustrates an example of a histogram of the % QT and %QTc.

[0029]FIG. 5 illustrates an example of hourly calculations for mean QTand QTc for a normal subject (solid=QT, cross-hatched=QTc).

[0030]FIG. 6 illustrates an example of hourly %QT and %QTc hour for aNormal Subject.

[0031]FIG. 7 illustrates an example of an increase in the 24-hour meanQT and QTc from baseline to peak dose (solid=baseline,cross-hatched=Peak Dose).

[0032]FIG. 8 illustrates an example in which the percentage of beatswith % QT and % QTc measurements greater than 450 ms were significantlyincreased from baseline to peak dose (solid=baseline, cross-hatched=PeakDose).

[0033]FIG. 9 illustrates an example of a histogram of % QT data frombaseline and peak dosing.

[0034]FIG. 10 illustrates an example of a histogram of % QTc data frombaseline and peak dosing.

[0035]FIG. 11 illustrates an example of average hourly QT and QTcmeasurements from a baseline recording (solid=QT, cross-hatched=QTc).

[0036]FIG. 12 illustrates an example of average hourly QT and QTcmeasurements from a peak dose recording (solid=QT, cross-hatched=QTc).

[0037]FIG. 13 illustrates an example of hourly values for % QT and % QTcat Baseline (solid=QT, cross-hatched=QTc).

[0038]FIG. 14 illustrates an example of hourly values for % QT and % QTcat peak dose (solid=QT, cross-hatched=QTc).

[0039]FIG. 15 illustrates an example of comparative histograms of % QTfor Normal, Drug Study, and ILQT Subjects.

[0040]FIG. 16 illustrates an example of comparative histograms of % QTcfor Normal, Drug Study, and ILQT Subjects.

[0041]FIG. 17 illustrates an example of five halter monitorings on thesame patient being treated with a pharmaceutical.

[0042]FIG. 18 illustrates an example of the % QT by minute, one hourafter maximum dose of a pharmaceutical.

[0043]FIG. 19 illustrates an example of the % QT by minute, four hoursafter maximum dose of a pharmaceutical.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0044] The following detailed description is of the best presentlycontemplated mode of carrying out the invention. This description is notto be taken in a limiting sense, but is made merely for the purpose ofillustrating the general principles of the invention. The scope of theinvention is best defined by the appended claims.

[0045] In a preferred embodiment, standard 24-hourAECG recordings may beobtained using either a Del Mar Scientific model 420 (Del Mar Avionics,Irvine, Calif.) or a Reynolds Tracker 11 (Reynolds Medical, England)recorder, for example. These recorders are commercially available andneed not be modified.

[0046] Analog signals from the cassette recordings may be digitized at12-bit resolution using a Reynolds PathFinder 700 Holter analyzer(Reynolds Medical, England) system, for example. The sampling rate ofthe algorithm may begin at 128 samples per second. For QT intervalanalysis, the sampling rate may preferably be increased to 128×128samples per second.

[0047] The digitized data may be reconstructed and displayed using aReynolds PathFinder 700 Holter analyzer on a high-resolution computermonitor. A QT analysis may preferably be started after an arrhythmiaanalysis has been completed and ectopic beats and artifacts have beenexcluded.

[0048] A QT interval analysis may be accomplished in the followingmanner: The onset of a Q-wave (Qb) may be defined and a cursor may beplaced at this point. The end of a T-wave (Te) may be defined and asecond cursor may be placed at this point. The data from the tape maythen be replayed at 60-times normal time, while the cursors on the Qband Te points may be monitored for stability. If either cursor waversfrom the Qb or Te points, the cursors may be replaced and the affectedportion of the data may be reanalyzed. The QT interval may be defined asthe time difference between the time points at Qb and Te. The QTintervals may be measured for the entire AECG recording on abeat-to-beat basis.

[0049] The peak of an R-wave may be detected and a third cursor may beplaced (Rp). Accordingly, each QT interval may be matched with thepreceding R-R interval. For a 24-hour recording, this may result inapproximately 100,000 beats for which a QT interval and an R-R intervalmay be defined. The data may then be output to a high-speed computer forpost-analysis processing.

[0050] In the examples described herein use was made of one AECGrecording from a normal volunteer, an on-treatment (peak-dose) recordingfrom a subject in a drug treatment study, and one recording from aninherited Long QT Syndrome (ILQT) patient. These recordings help todemonstrate the potential effectiveness of a % QT method in accordancewith the present invention over simply analyzing the mean QT intervalmeasurement. All subjects were male, less than 60 years old.

[0051] In the examples described herein QTc was calculated by removing atime-series of the QT and preceding R-R intervals to a high-speedcomputer with both a fast processor and adequate disk storage space. Foreach QT interval, a QTc may be calculated using Bazett's correctionformula. This formula may be stated as:

QTc=QT (msec)/Sqr (R-R)

[0052] Calculation of % QT and % QTc may be achieved by firstconstructing a two-dimensional, time-series array (bin) at about 0.01second intervals. In a preferred embodiment the bin-array may range fromabout 0.30 seconds to about 0.70 seconds, with additional bins designedto capture beats with QT or QTc measurements of less than 0.30 secondsor greater than 0.70 seconds. The QT and QTc intervals may beindividually placed in the bins according to their measurement. In apreferred embodiment the bins may be constructed in accordance with theformulas expressed in FIG. 1 and FIG. 2. The percentage of beats in eachbin may be calculated by comparing the number of beats in each bin tothe overall number of beats used in the analysis. A construction of a %QT system in accordance with this embodiment of the present inventionallows for analysis of a variety of upper-limits (threshold points)based on patient population and condition under investigation. In thisembodiment a threshold point of about 450 ms was analyzed.

[0053] In addition to an overall (24-hour) analysis, data for each AECGrecording may also be analyzed by comparing daytime (about 0700 to about2300) to nighttime (about 2300 to about 0700). Means for QT intervalmeasurements may be calculated for each hour and the beat-to-beat datamay be grouped by hour for ease of display. Differences may be comparedfrom day to night using a student's West.

[0054] A % QT and % QTc may be calculated for each hour. Daytime andnighttime values (circadian variation) may be compared using a student'st-test.

[0055] To assess the accuracy (reliability) of computer-generated QTinterval detection in accordance with the present invention, an AECGrecording may be scanned ten times using a Holter analyzer. The overallmean QT measurement may be calculated for each analysis, as well as thestandard error of the ten individual mean measurements.

[0056] Validity may be assessed by having two reviewers select 1000 AECGbeats from the analysis and measuring the QT intervals by hand. Themanual measurements may be compared against each other and against acomputer measurement by a student's +-test.

[0057] To ensure data quality, a trained technician may visually monitorthe stability of the fiducial point of the AECG during analysis. FIG. 3represents a computer-generated QT interval with cursors in place. Inthe present invention the visual end of the T-wave may be used in amanner analogous to a manual measurement. A single AECG recording wasanalyzed 10 times. Table 1 shows the overall means for each analysis andthe mean and standard error for the group. The standard error of the tenrecordings was 0.1724. Thus, the computer-generated QT intervalmeasurements were reproducible reflecting a 0.001% error.

[0058] A sample of 1000 beats was selected for manual measurement. Thesebeats were measured by two reviewers and the results correlated betweenthe reviewers' measurements and the automated measurements. Thecorrelation coefficient between the reviewers' observations and thecomputer-generated values was 0.938. These results are shown in Table 2.

EXAMPLE 1 Normal Subject

[0059] The normal subject had a mean QT interval measurement of 342 mswith a standard deviation of 37 ms. The mean QTc measurement was 414 mswith a standard deviation of 13 ms. Both the mean QT and mean QTc wereconsidered within the normal range (Table 3). When % QT>450 ms wascomputed, 0.19% (n=173) of the beats had a QT interval measurement ofgreater than 450 ms and 4.65% (n=4224) of the beats had a QTcmeasurement of greater than 450 ms. FIG. 4 shows the histogram of the %QT and % QTc for this recording. Thus, 4.65% of the beats recorded onAECG had QTc intervals greater than 450 ms.

[0060] When analyzed for circadian differences, a change was seen in theboth the mean QT interval and the mean QTc (p<0.001, p<0.001,respectively). Table 4 contains the means and standard deviations of thecircadian variation data. More AECG beats at night had QT and QTcintervals greater than 450 ms. FIG. 5 graphically depicts the hourlycalculations for mean QT and QTc, while FIG. 6 graphically depicts thehourly % QT and % QTc.

EXAMPLE 2

[0061] Drug Induced Prolonged QT Interval

[0062] One application for a % QT method in accordance with the presentinvention is to observe the effect of a drug dose on the QT intervalmeasurement. This may be done by comparing the baseline QT interval tothe QT interval after dosing.

[0063] In Example 2 baseline and peak-dose data were taken from asubject in a clinical research trial. The means and, standard deviationsof the baseline and peak dosing recordings are shown in Table 3. Whilethere was an increase in the 24-hour mean QT and QTc from baseline topeak dose (FIG. 7), both mean QT and QTc were considered normal at thebaseline and peak dose. The % QT method shows that the percentage ofbeats with QT and QTc measurements greater than 450 ms weresignificantly increased from baseline to peak dose. (FIG. 8). Ahistogram % QT data from baseline and peak dosing is shown in FIG. 9. Ahistogram % QTc data from baseline and peak dosing is shown in FIG. 10.

[0064] The circadian rhythm of the subject's QT interval measurementswas also changed. FIG. 11 shows the average hourly QT and QTcmeasurements from the baseline recording. FIG. 12 shows the hourly QTand QTc measurements from the peak dose recording. Table 3 shows the dayversus night values. Even with the increase in QT and QTc intervalsduring the peak dose, the values during nighttime were longer thanduring the daytime hours (p<0.001, p<0.001, respectively). This was truefor the % QT and % QTc as well. FIGS. 13 and 14 show the hourly valuesfor % QT and % QTc, respectively.

EXAMPLE 3 ILQT Patient

[0065] Data for the QT and QT measurements for an ILQT patient ispresented in Table 3. The means for both QT and QTc are consideredwithin normal clinical limits. There was, however, an increase in the %QT and % QTc over the normal subject, and baseline measurements of thedrug-study subject.

[0066]FIGS. 15 and 16 show comparative histograms of for the threesubjects. The % QT is shown in FIG. 15 and the % QTc is shown in FIG.16. In both histograms, the ILQT subject has a higher percentage ofbeats greater than 450 ms.

[0067] Despite a lack of standardization, it is well understood thatpatients who have a propensity for the development of ventriculartachycardia sometimes display prolonged QT intervals. Using the presentinvention, patients with ILQT have displayed more abnormal QT and QTcintervals as assessed by AECG analysis.

[0068] In a preferred embodiment, the present invention represents a newmethod and apparatus for quantifying the QT interval over a period oftime. The invention allows a quantitative assessment of the number ofbeats with QT and QTc intervals of specific lengths. For example, theinvention allows identification of the number of cardiac cycles with theQT interval measured at 0.45 to 0.46 seconds. This allows creation of anindex that displays the number of cardiac cycles with QT intervalsgreater than 0.45 seconds. In addition, this method and apparatus allowsthe identification of the number of cardiac cycles with QTc measurementsgreater than 0.45 seconds. Using the present invention, the thresholdcan be set by the operator. In the particular study described herein, athreshold point out 0.45 seconds was used.

[0069] In a preferred embodiment, the method and apparatus may make useof high-speed computer processors, such as the Pentium II processor, andlarge capacity data-storage media. In a preferred embodiment a 266mHzPentium II processor with an 8.6-gigabyte hard drive may be used toanalyze and store the large data files.

[0070] There is some controversy regarding the use of correctionformulas to calculate QTc measurements. While approximately twelvedifferent formula are available for correction of the QT interval, in apreferred embodiment of the present invention Bazett's formula has beenused when referring to QTc. The present invention is capable ofretaining the raw beat-to-beat variability data regardless of thecorrection formula used. A preferred embodiment of the computer programallows insertion of other formulas, as knowledge of the dynamic natureof the QT interval improves.

[0071] The present invention demonstrates that there is an incidence ofprolonged QT and QTc intervals in ostensibly normal subjects. The twonormal subjects showed that when considering a 24-hour period, up to 5%of the QTc intervals may exceed 450 milliseconds. Using both 12-lead ECGand 24-hour AECG recordings, others have reported frequent prolonged QTand QTc intervals in normal subjects when looking at random beats. Thisfinding suggests that random observation of the QT interval on theresting 12-lead ECG should be viewed with caution in assessing potentialQT and QTc prolongation occurring both spontaneously and with drugtherapy. The observation that prolonged QT intervals can occur in normalsubjects has led us to develop the % QT and % QTc measurements. Thesequantitative assessments of the number of beats with various degrees ofQT and QTc prolongation are more likely to accurately measure the QTinterval on 24-hour AECG recordings than random measurements taken fromthe resting 12-lead ECG. Further study may be useful to correctlyidentify dynamic changes in QT and QTc interval measurements in normalsubjects stratified by age.

[0072] The QT interval has been shown to vary with both heart rate andautonomic function. The applicants have observed that there is a timelag between an increase in heart rate and a subsequent reduction in thelength of the QT interval. This lag phase has been reported by others aslasting one minute to three minutes in length. See Franz M R, Swerdlow CD, Liem B L: Cycle-length dependence on human action potential durationin vivo: effects of single extra stimuli, sudden sustained rateacceleration and deceleration, and different steady-state frequencies. JClin Invest 82:972, 1988; Coumel P, Fayn J, Maison-Blanche P, Rubel P:Clinical relevance of assessing QT dynamicity in Holter recordings. JElectrocardiol 27(suppl):62, 1994. Since the QT interval is under thecontrol of both sodium and potassium channels, this mechanism may varyin terms of time from one individual to another. This time lag may showmore variability in subjects with genetic defects in their sodium,potassium, and calcium channels.

[0073] Applicants have analyzed more than 80,000 beats per AECGrecording to assess variation and dynamic changes in QT and QTcintervals. Applicants data suggest that an automated measurementtechnique, in addition to being able to process more AECG measurementsmore quickly, is more reliable than manual measurements of the QT andQTc interval.

[0074] Percent QTc measurement in accordance with the present inventionallows for a quantitative assessment of the number of beats in a 24-hourAECG recording that exceeds some pre-selected threshold value. In apreferred embodiment of the present invention the applicants used 0.45seconds as the threshold.

[0075] The present invention, in a preferred embodiment, is directed toa method and apparatus for the quantification of beat-to-beat QT and QTcinterval measurements from ambulatory electrocardiographic recordings.This method and apparatus tends to be superior to averaging, as itretains the raw beat-to-beat variability that may be useful incalculating a subject's risk of sudden death from ventriculararrhythmias.

[0076] A QT binning technique in accordance with the present inventionmay be used to provide information about the effects of apharmaceutical. For instance, in the example illustrated in FIGS. 17-19,a patient had five separate Holter monitorings. The first was a baseline monitoring. Then three doses and a placebo were provided to thepatient in random order and the patient was monitored. Using a binningmethod in accordance with the present invention, an increase in the QTinterval could be demonstrated better than by simply averaging or justmeasuring a QT interval. For instance, in the example illustrated inFIGS. 18 and 19, there was no beats greater than 450 milliseconds untilabout 10:43 AM. The dose was given at about 9:50 AM, so these graphsindicate that it took the dose about one hour to work. Then, after aboutone hour, the percentage of beats greater than 450 millisecondsincreased to between about 80% and about 100% and then dropped off aftera number of hours, at about 4:00 PM.

[0077] This information indicates that the drug prolonged the QTinterval. Using a prior art averaging technique based upon a singlemeasurement, like a 12 lead ECG, if the number of beats or thepercentage of beats greater than 450 milliseconds was not 100%, thenthere would be only a random chance of getting the beats andcharacterizing the beats properly.

[0078] Although the preferred embodiment of the present invention hasbeen described herein with respect to measurement and analysis of the QTinterval, it will be recognized that a method and apparatus inaccordance with the present invention may also be useful in themeasurement and analysis of a wide variety of other ECG and relatedbiologically significant intervals. For example, with reference to theexamples of ECG fiducial points illustrated in FIG. 3, the presentinvention may be useful for the measurement and analysis of, withoutlimitation, the PR interval, the RR interval, the QT interval, the STinterval, the QRS duration, the JT interval, the QTA apex, and theinterval between P beginning and P end.

[0079] In a preferred embodiment, the method takes discreet measurementsand discreet intervals and places them into a time series bin or anamplitude series bin. For example, all of the PR intervals in a samplecould be selected and coded according to their length and then put theminto bins. Each bin could be characterized by a frequency. The sameanalysis could be performed using an RR interval, or a QT interval.

[0080] With an ST interval it may be preferable to use an amplitudeseries bin rather than a time series bin. An ST may be depressed orelevated relative to base line. That depression or elevation may bemeasured and put into amplitude bins.

[0081] The presently disclosed embodiments are to be considered in allrespects as illustrative and not restrictive, the scope of the inventionbeing indicated by the appended claims, rather than the foregoingdescription, and all changes which come within the meaning and range ofequivalency of the claims are therefore intended to be embraced therein.TABLE 1 Means and standard errors from 10 separate scans of the sameHolter recording 1 343.6976 2 344.2968 3 343.8468 4 345.5889 5 343.83066 344.0974 7 343.6976 8 344.0395 9 344.1455 10 344.1611 Average344.14018 standard error 0.1724

[0082] TABLE 2 Validation of Hand Measures versus Computer Measures ofthe QT Interval Example Data Set 1000 samples measured QT Computer #Boxes Hand QT hand 0.39 10 0.4 0.37 9 0.36 0.36 9 0.36 0.35 8.5 0.340.38 9.5 0.38 0.39 10 0.4 0.4 10 0.4 0.4 10 0.4 0.4 9.7 0.388 0.405 10.10.404 0,405 10 0.4 0.352 8.5 0.34 0.36 8.5 0.34 0.36 8.5 0.34 0.4 9.50.38

[0083] TABLE 3 Means and Standard Deviations by Subject Subject QT AvgQTc Avg % QT Avg % QTc Avg Normal 342 ± 36 414 ± 21 0.19 ± 0.26  4.65 ±12.08 Clinical 360 ± 20 384 ± 13 0 ± 0 0.61 ± 3.39 Research (baseline)Clinical 416 ± 24 421 ± 22 5.29 ± 19   12 ± 21 Research (peak does) ILQT437 ± 52 420 ± 19 34.44 ± 48.5  12.51 ± 16.98

[0084] TABLE 4 Means and Standard Deviations of QT and QTc Intervals Dayvs. Night Subject QT Day QT Night QTc Day QTc Night Normal 322 ± 14 392± 20 415 ± 12 412 ± 14 Clinical 349 ± 15 375 ± 18 387 ± 18 379 ± 21Research (baseline) Clinical 408 ± 26 426 ± 11 428 ± 26 409 ± 19Research (peak does) ILQT 403 ± 43 476 ± 35 419 ± 29 426 ± 27

1. A quantitative method of measuring a cardiac function interval, themethod comprising: collecting, over an extended period of time,beat-to-beat data representative of a cardiac interval, eachbeat-to-beat data having a value, defining a plurality of bins, each oneof the plurality of bins having a defined value range, organizing eachof the collected data into one of the plurality of bins in accordancewith the value of the data and the value range of the bin, andcalculating a percentage of data in each bin based upon the quantity ofdata in each bin.
 2. The method of claim 1 wherein the step ofcalculating comprises calculating a percentage of data exceeding adefined threshold.
 3. The method of claim 2 wherein the definedthreshold comprises a time threshold
 4. The method of claim 2 whereinthe threshold comprises an amplitude threshold.
 5. The method of claim 1wherein the step of collecting data comprises obtaining an ambulatoryelectrocardiographic monitoring recording.
 6. The method of claim 1wherein the cardiac function interval comprises at least one of a QTinterval, a QTc interval, a PR interval, an RR interval, an ST interval,a QRS duration, a JT interval, a QTA apex, and an interval between Pbeginning and P end.
 7. A device for quantitatively measuring a cardiacfunction interval, the device comprising: means for collecting, over anextended period of time, beat-to-beat data representative of a cardiacinterval, each beat-to-beat data having a value, means for defining aplurality of bins, each one of the plurality of bins having a definedvalue range, means for organizing each of the collected data into one ofthe plurality of bins in accordance with the value of the data and thevalue range of the bin, and means for calculating a percentage of datain each bin based upon the quantity of data in each bin.
 8. The deviceof claim 7 wherein the means for calculating comprises means forcalculating a percentage of data exceeding a defined threshold.
 9. Thedevice of claim 8 wherein the defined threshold comprises a timethreshold.
 10. The device of claim 8 wherein the threshold comprises anamplitude threshold.
 11. The device of claim 7 wherein the means forcollecting data comprises ambulatory electrocardiographic monitor. 12.The device of claim 7 wherein the cardiac function interval comprises atleast one of a QT interval, a QTc interval, a PR interval, an RRinterval, an ST interval, a QRS duration, a JT interval, a QTA apex, andan interval between P beginning and P end.
 13. A method of measuring aneffect of a pharmaceutical on a subject, comprising: providing apharmaceutical to the subject, collecting, over an extended period oftime, beat-to-beat data representative of a cardiac interval of thesubject, each beat-to-beat data having a value, defining a plurality ofbins, each one of the plurality of bins having a defined value range,organizing each of the collected data into one of the plurality of binsin accordance with the value of the data and the value range of the bin,and calculating a percentage of data in each bin based upon the quantityof data in each bin.
 14. A quantitative method of measuring a cardiacfunction interval, the method comprising: collecting, over an extendedperiod of time, beat-to-beat data representative of a cardiac interval,each beat-to-beat data having a value, stratifying the collected data,based upon the value of the collected data, in accordance with aplurality of defined bins, each one of the plurality of bins having adefined value range, and calculating a percentage of data in each binbased upon the quantity of data in each bin.
 15. A device forquantitatively measuring a cardiac function interval, the devicecomprising: means for collecting, over an extended period of time,beat-to-beat data representative of a cardiac interval, eachbeat-to-beat data having a value, means for stratifying the collecteddata, based upon the value of the collected data, in accordance with aplurality of defined bins, each one of the plurality of bins having adefined value range, and means for calculating a percentage of data ineach bin based upon the quantity of data in each bin.